EFRI DCheM: Distributed Manufacturing of Personalized Medicines

按每质量一美元计算，活性药物成分（api）可能是世界上最有价值的化学物质，但所服用药物中的大部分api没有被人体吸收，进入供水系统，可能危害人类健康和环境。与此同时，尽管个性化医疗科学和数字化增材制造技术取得了快速发展，但每年价值数万亿美元的制药行业仍保留着其百年历史的制造流程，并使用可能容易被篡改、污染和破坏的供应链和分销模式。为了解决这个问题，研究人员和药物制造商已经开始开发3D打印方法，以及从其他行业借鉴的技术（例如薄膜涂层），用于药物配方、剂量定制和释放剖面工程。然而，基本的挑战仍然存在于材料相容性，溶剂或基质材料中的成分分散，过程控制和可扩展性。这个基础研究项目旨在通过在增材制造、分子和结晶建模、表面科学和工程以及患者特异性体外疾病模型方面的几项新突破来解决这些挑战。该项目将培训不同背景的学生，包括妇女和少数民族，以及与病人护理和安全、公共卫生、药品费用、监管法律和做法有关的学生。这个基础研究项目将引入一种全新的药物配方和分布式制造方法，提供控制晶体结构、共结晶和适应不同递送载体的新方法。目前，基于预测模型的有机结晶工艺设计还处于相对初级阶段。同样，共结晶过程需要进一步的工作来系统化共晶选择和预测共晶形成的条件。这里使用的新型无溶剂工艺为开发新型药物共结晶研究工具提供了可能性，也为可扩展的共结晶制造提供了途径。控制表面润湿性模式的技术平台能够实现低成本的溶解测定，结合类器官测定，将为现场验证和产品质量控制创造新的范例，这将在分布式制造环境中特别有益。使用的类器官分析可以在人体试验之前在更现实的细胞微环境中快速测试新药物。这项研究将有助于加快从药物开发到生产和分销的时间，并有助于防止潜在危险的副产品或污染物接触到患者。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

On a dollar per mass basis, active pharmaceutical ingredients (APIs) are perhaps the most valuable chemicals in the world, and yet much of the mass of APIs in drugs taken is not absorbed in the body, entering the water supply and potentially harming human health and the environment. At the same time, despite rapid advances in the science of personalized medicine, and digital, additive manufacturing, the trillion-dollar-per-year pharmaceutical industry retains its century-old manufacturing processes and uses supply chain and distribution models that are potentially prone to tampering, contamination, and disruption. To address this problem, researchers and drug manufacturers have begun developing 3D printing approaches, as well as techniques borrowed from other industries (e.g. thin-film coatings) for drug formulation, dose customization, and release profile engineering. However, fundamental challenges remain with material compatibilities, ingredient dispersion in solvents or matrix materials, process control, and scalability. This fundamental research project aims to address these challenges by converging several new breakthroughs in additive manufacturing, molecular and crystallization modeling, surface science and engineering, and patient-specific in vitro disease models. This project will train students of diverse backgrounds, including women and minorities, and those concerned with patient care and safety, public health, drug costs, regulatory law and practices.This fundamental research project will introduce a radically new approach to drug formulation and distributed manufacturing, offering new means of controlling crystalline structure, cocrystallization, and adaptation to different delivery vehicles. Currently, predictive model-based process design for organic crystallization processes is still in relative infancy. Likewise, processes for cocrystallization require further work to systematize coformer selection and prediction of conditions for cocrystal formation. The novel, solvent-free process used here offers possibilities for developing novel pharmaceutical cocrystallization research tools, as well as a path to scalable cocrystal manufacturing. The technology platform of controlled surface wettability patterns to enable low-cost dissolution assays, combined with the organoid assays will create new paradigms for on-site validation and control of product quality, which will be particularly beneficial in a distributed manufacturing setting. The organoid assays used could enable rapid testing of new medications in more realistic cellular microenvironments prior to human trials. This research will facilitate the path to accelerating the time from drug development to manufacturing and distribution, and help prevent potentially dangerous by-products or contaminants from reaching patients.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.